Transition metal complexes as linkers

ABSTRACT

The invention relates to new traceless linkers which use transition metal complexes to link a pi-orbital containing substrate for subsequent synthesis by, for example, combinatorial chemistry or multiple parallel synthesis (MPS) to a support.

The invention relates to new traceless linkers which use transitionmetal complexes to link a π-orbital containing substrate for subsequentsynthesis by, for example, combinatorial chemistry or multiple parallelsynthesis (MPS) to a support.

Combinatorial chemistry and MPS are techniques that are of great valuein the efficient production of large numbers of molecules. Such largecollections of molecules are of use in screening for useful propertiesor effects. The development of combinatorial chemistry and of MPS hasbeen greatly facilitated by the use of solid-phase-synthesis in whichsubstrate molecules are covalently attached to a solid support. Theproduct of the reaction can be isolated by mechanically separating thesolid support from the other components of the reactions and the productseparated from the solid support by, for example, chemical cleavage. Thewhole process can be carried out quickly and efficiently and in manycases can be automated.

Members of a set of molecules made by combinatorial chemistry or MPSwill have a recognisable common framework inherited from each differentsubstrate and optionally modified during the combinatorial chemicalsteps. Disposed about the framework are the variable parts that derivefrom combinatorial modification of the substrate, for instance bycombinatorial refunctionalisation of its functional groups. It is thevariation in these parts that determines the diversity of the collectionof molecules.

In most examples of solid-phase-synthesis the substrate is attached tothe solid support through a covalent bond formed by functional groups onthe substrate and support, for example by the formation of a carboxamidegroup between the support and the substrate.

This has three main limitations:

1. The functional group that is used to bind the substrate could havebeen used to introduce further variable reagents. This lost opportunityis a combinatorial reduction in the potential diversity of the moleculesproduced.

2. Although the object is to produce sets of compounds of greatdiversity in order to screen for useful properties or effects, thefunctional group that is linked to the support is a feature that allmembers of the combinatorial set of compounds share so that thediversity of the compounds produced is compromised by this commonfeature.

3. The chemistry required to attach a molecule through a functionalgroup to a support varies as the functional group varies. In general,each different functional group will need to be linked to a support thathas been specially prepared to react with it. Each differently linkedfunctional group will need a different chemical treatment to release itfrom the support. Each different linking functional group will placedifferent restrictions on the type of chemistry which can be carried outon the supported molecules.

A number of attempts have been made to link substrates to supports bylinkers which are designed to be traceless, i.e. the linker leaves nofeature on the final product. Traceless linkers are those that are notbeing used as a protecting group for a specific functional group, andthat are removed from the product molecules as part of the process ofreleasing the molecules from the support. The traceless linkers reportedso far (e.g Sucho Leiki I. Tetrahedron Lett., (1994), 35, 7307: CheneraB et. al., J. Am. Chem. Soc., (1995), 117, 11999: Plunkett, M. S. et.al., (1995), 60, 6006) have been developed for specific applications andare either of limited generality or require specific chemical synthesisof every variation of the first supported reagent, or leave behind acharacteristic functional group that limits the diversity of themolecules produced. For instance, the existing examples of acid labilearylsilane linkers or reductively cleavable alkylthioether linkers arelimited in scope and synthetically limited in accessibility. Acid labilearylsilane linkers are obtained by separate functionalisation orrefunctionalisation of an aromatic ring of each linked substrate andafter acid-induced cleavage of the linker every product contains ahydrogen atom at the position previously occupied by the silanefunctional group. The alkylthioether linkers similarly require aseparate functionalisation or refunctionalisation of each linkedsubstrate and cleavage of the thioether functional group thatconstitutes the link results in a reduction of the degree offunctionality of the product.

Organometallic chemistry is a subset of chemistry dealing with the areaof metals containing ligands bonded through a carbon atom. The area isextremely diverse due to the number of different interactions possiblewith the metal group, thus allowing any number of diverse compounds tobe produced. One form of interaction between a metal and an organicgroup is in the form of a π-complex between an organic ligand having aπ-bond, such as is present on an olefinic or an aromatic compound, and atransition metal. A characteristic of such complexes is that the bondbetween the transition metal and the organic group is formed to theπ-orbitals of the organic group and not the σ-orbitals of the framework.Although the reactivity of the π-orbitals is thereby changed theconnectivity of the framework of the organic group remains intact. Suchπ-bonded transition metal complexes constitute a well-known class ofcompounds that is described, for instance, in “ComprehensiveOrganometallic Chemistry” Wilkinson G., Stone G. A., and Abel E. W.Eds., Pergamon Press, 1982, Oxford, U.K. and in “Transition Metals inthe Synthesis of Complex Organic Molecules” Hegedus L. S., UniversityScience Books, 1994, Mill Valley, Calif., USA. Examples of suchcomplexes with common organic compounds include (1) (“ComprehensiveOrganometallic Chemistry” Vol. 3, Chapter 26.2, Tables 10 and 111003-1005) and (2) (“Transition Metals in the Synthesis of ComplexOrganic Molecules” Chapter 7.3, 221).

Transition metal complexes serve as masking or protective groups forπ-bonded ligands of organic compounds. Soluble π-bonded complexes ofarenes with chromium(0), of alkynes with cobalt(0), dienes and enoneswith iron(0) and olefines with iron (+1) are well known and have beenused as protective groups for organic groups during functional groupmanipulation.

In addition π-bonded transition metal complexes have been immobilised onsolid polymer supports via a polymer attached phosphine ligand for useas catalysts in organic and polymer chemistry. The polymer support isneeded so as to aid isolation of the catalyst from the reaction mixture.

We have now found that transition metal complexes can be used astraceless linkers of remarkable simplicity, generality, and utility.These transition metal complexes may be used to π-bond unsaturatedorganic substrate ligands, such as arenes, alkynes, alkenes, and dienes,to a support for use in combinatorial chemistry and MPS.

The invention is illustrated below.

A feature of the traceless linker illustrated is its versatility: notonly can the transition metal attach to a wide variety of π-orbitalcontaining substrates, to allow an enormous diversity of librarycomponents to be synthesised, but it can also be attached to a greatvariety of supports. The transition metal+linker ligand constitutes a“traceless” linker because no trace of the link in the form of acharacteristic functional group remains on the chemically modifiedsubstrate molecule after it has been released, as the product, from thesupport. This is true also in cases where the original π-orbitalcontaining framework (an unsaturated system) of the substrate ligand hasitself been modified during the synthesis or cleavage of the productsince the modification to the original π-orbital containing framework isa modification to the core or backbone of the molecule rather than toits functional groups. Therefore all the functional groups of asubstrate supported in this way are available for diverse modification.

Presented as a first feature of the invention is the use of a transitionmetal complex as a traceless linker between a support and an unsaturatedorganic molecule by the formation of a π-complex bond between thetransition metal and the unsaturated organic molecule and attaching ofthe transitional metal to the support before during or after theformation of the π-complex bond, which unsaturated organic molecule isthen, preferably, a substrate for further chemical modification andeventual release from the traceless linker.

A further feature of the invention is a traceless linker system whichcomprises a transition metal complex attached to a support which iscapable of forming a π-complex bond with an unsaturated organicmolecule.

A further feature of the invention is a traceless linker system whichcomprises a transition metal complex attached to a support and anunsaturated organic molecule attached to the transition metal through aπ-complex bond.

A further feature of the invention is a method of attaching to a supportvia a transition metal complex traceless linker an unsaturated organicmolecule, which is then, preferable, a substrate for further chemicalmodification and eventual release from the transition metal complex,which method comprises one of the following alternative first steps:

(1) bonding the transition metal complex, which has bound to it througha π-complex bond the unsaturated organic substrate molecule, with thesupport, where the transition metal complex, support or both has a groupcapable of forming a bond, linker or interaction between the transitionmetal complex and the support;

(2) bonding the unsaturated organic substrate molecule with thetransition metal complex, which is bound to the support, by forming aπ-complex between the supported transition metal and the unsaturatedorganic substrate; or

(3) converting an organic molecule which is σ- or π-bonded to thetransition metal, which is bound to the support, to form a π-complexbetween the supported transition metal and the unsaturated organicsubstrate molecule.

Preferably specific preferred later steps include subsequent synthesison the bound unsaturated organic substrate, where synthesis may beeither by combinatorial chemistry or by multiple parallel synthesistechniques, and removal of the product from the support.

Thus formed is a π-substrate-transition metal-support complex in whichthe π-ligand, or ligands, is the substrate for a chemical reaction, andat least one of the other ligands of the complex is the linker groupbetween the transition metal π-complex and the support. Examples ofsuitable complexes, where L is the linking ligand and S is the support,are:

1. π-Arene Cr(CO)₂L-S complexes as supported arene substrate.

2. η²-Alkyne Co₂(CO)₅L-S complexes as supported alkyne substrate.

3. η²-Alkene FeCp(CO)L⁺-S and η⁴-diene Fe(CO)₂L-S complexes as supportedolefin substrate.

Where Cp=η⁵-cyclopentadienyl anion

The support may be insoluble, such as a polymer or resin, soluble, suchas a polyethylene glycol (PEG) which can be selectively precipitated asrequired, or fluorous phases, which show temperature dependentimmiscibility with common organic solvents. It will be understood thatit is possible to complex the unsaturated organic molecule to thetransition metal at any stage, for example it may be convenient to buildthe transition metal complex onto the support prior to complexation withthe unsaturated organic molecule or to complex the unsaturated organicmolecule with the transition metal prior to attachment to the support.Alternatively the π-unsaturated organic molecule transition metal complemay be formed in situ by conversion of, for example, a σ-organicmolecule transition metal complex.

The substrate ligand may be any unsaturated organic molecule containingat least one functional group that can be modified in a chemicalsynthesis and a π-orbital system that is capable of forming a π-complexwith a suitable transition metal complex. The π-orbital system ispreferably an integral part of the structural framework of both thesubstrate and the product rather than of one of the functional groups ofthe substrate or product.

The linking group can be any functional group capable of complexing withthe transition metal and joining to the support. The linker group ispreferably selected from those ligands known to form a strong bond tothe transition metal. Suitable ligands include phosphines, phosphites,and isonitriles. A further embodiment of the reaction is that a singlesupport bearing a common linking ligand can be used to support a widevariety of substrates through different transition metal complexes.

An additional embodiment of the invention is that the transition metalπ-complex may itself take part in the chemical transformation. Oneexample occurs where the formation of the complex of the unsaturatedfragment (a π-system) of the substrate changes the reactivity ofneighbouring functional groups to facilitate reactions that wouldotherwise be difficult to achieve; for instance the ready displacementof an aryl halide by diverse nucleophiles in π-arene Cr(CO)₂L complexes.A further example occurs where the unsaturated fragment (a π-system) ofthe substrate ligand itself undergoes a chemical reaction to produce anew unsaturated fragment (a π-system) of a modified substrate; forinstance in the reaction of [η⁵-dienylFe(CO)₂L]⁺ complexes withcarbanions to give η⁴-dieneFe(CO)₂L complexes. A further example occurswhere the unsaturated fragment (a π-system) of the substrate liganditself undergoes a chemical reaction to produce a modification of theunsaturated fragment that no longer complexes to the supportedtransition metal complex so that concomitant release of the productligand occurs to give the unsupported product; for instance in thePaulson-Khand reaction of η²-alkyne Co₂(CO)₅L complexes to givecyclopentenones.

A suitable transition metal is one capable of forming a cleavable stableπ-complex contemporaneously with the π-orbital containing substrate andother ligands, at least one of which (the linker ligand) is able to becovalently attached to the solid support. The preferred transition metalvaries according to the nature of the substrate ligand. Factorsaffecting the choice of suitable transition metal are known to thoseskilled in the art and are described inter alia in “ComprehensiveOrganometallic Chemistry” Wilkinson G., Stone G. A., and Abel E. W.Eds., Pergamon Press. 1982, Oxford, U.K.

Another additional embodiment of the invention is that when a transitionmetal complex linked to the support contains at least one exchangeableligand other than the linker and substrate ligands, this exchangeableligand can be replaced in part at each stage of the chemicalmodification of the substrate ligand by treatment with trace quantitiesof a tagging ligand. The unique combination of tagging ligands thusspecifies the chemical history of the substrate linked to the supportand acts as a label for e.g. resin beads in combinatorial splitsynthesis.

The tagging ligands are chosen from a set of similar but diversecompounds such as triaryl phosphines or halogenated alkyl or arylphosphites, where each tagging molecule is unique to each of thedifferent chemical modification steps used in the overall synthesis.

The tagging techniques described above may be practised not only on thetransition metal complex linking the substrate to the support but toadditional transition metal complexes on the support added exclusivelyfor tagging. Alternatively the tagging techniques described above may beused alongside other linker techniques. Suitable tagging ligands aredetectable and identifiable by mass spectrometry.

Presented as a further feature of the invention is a method for tagginga support within a chemical synthesis comprising for each reaction stepdesired to be labelled contacting a transition metal complex containingan exchangeable ligand bound to the support with a tagging ligand uniquefor the reaction being performed.

Presented as a further feature of the invention is a method for tagginga support within a chemical synthesis comprising for each reaction stepdesired to be labelled contacting a transition metal complex with areactive group capable of making an analysable modification on one ofthe ligands of the transition metal complex unique for the reactionbeing performed.

It will be understood that the tagging reagents, whether a taggingligand or reactive group, are introduced in such a way that only a smallfraction of the sites that may be tagged are modified in any singlestep. Used in this way several different tagging reagents may be addedseparately and sequentially to unambiguously identify each of a sequenceof several chemical reactions without any of the tagging reagentssignificantly interfering with the effectiveness of any of the othertagging reagents or with the chemistry being carried out on thesupported π-complex of the substrate.

A cleavable stable π-complex is one in which the complex of thesubstrate ligand and the transition metal is stable to storage and useand from which the product ligand can be released. Preferably theunsaturated fragment (a π-system) will be unchanged. Factors affectingthe choice of suitable cleavable complexes are known to those skilled inthe art and are described inter alia, in “Comprehensive OrganometallicChemistry” Wilkinson G., Stone G. A., and Abel E. W. Eds., PergamonPress, 1982, Oxford, U.K.

The product ligand (unsaturated organic molecule with modifiedfunctional groups) may be cleaved from the complex to give the productby any effective method that does not damage the structural integrity ofthe product. Suitable methods include thermal, photochemical, andoxidative cleavage.

The substrate transition metal π-complex is located on the surface orthroughout the support in such a way that it is accessible to theconstituents of a reaction that is to be carried out on the substrateligand.

A-π-bonded transition metal complex with an exchangeable ligand can bepreformed and attached to a supported ligand to give a supportedπ-bonded transition metal complex, by a simple process of ligandexchange well known to those skilled in the art.

A transition metal complex with exchangeable ligands can be attached toa supported ligand to give a supported transition metal complex withexchangeable ligands and these ligands can be replaced with thesubstrate ligand (unsaturated organic molecule) with an unsaturatedfragment (a π-system), another simple process of ligand exchange wellknown to those skilled in the art.

A-π-bonded transition metal complex with a functionalised linking ligandcan be preformed and attached to a support by refunctionalisation of thefunctionalised linking ligand to give a supported π-bonded transitionmetal complex, for instance by coupling a carboxy functionalised linkingligand to an amino-functionalised support by amide bond formation.

A supported transition metal complex containing a ligand may bechemically modified so that the ligand is converted into a π-bondedsubstrate ligand of a π-bonded transition metal complex; for instance inthe conversion by Doetz reaction of supported σ-carbeneCr(CO)₄Lcomplexes into π-arene Cr(CO)₂L complexes of supported arenes (σ-complexto π-complex).

A supported transition metal complex containing a π-bonded ligand may bechemically modified so that the π-bonded ligand is converted into aπ-bonded substrate ligand; for instance in the conversion of[η⁵-dienylFe(CO)₂L]⁺ complexes into η⁴-dieneFe(CO)₂L complexes (π-bondedcomplex to another π-bonded complex).

FIG. 1. Illustrates joining of a π-bonded transition metal substratecomplex to a support via ligand exchange, a subsequent reaction step tothe substrate ligand and later release of the product ligand from thetransition metal polymer complex.

EXAMPLES Photolysis of Diphenylphosphinopolystyrene withTricarbonyl(arene) Chromium Complex

Diphenylphosphinopolystyrene¹, (3 mmol g⁻¹, 1.59 g, 4.77 mmol) wasstirred in tetrahydrofuran (THF) (350 mL) for 1 hour before addition oftricarbonyl[4-(p-methoxyphenyl)butan-2-one]chromium (1.65 g, 5.25 mmol).The mixture was irradiated (125 W Phillips Hg-vapour lamp) for 3 hours,and then allowed to react in the dark for a further 1 hour. The reactionmixture was transferred by cannula into 1 L round-bottomed flask, andthe solid allowed to settle. The supernatant solvent was removed bycannula, and the residual solid washed with THF (2×100 mL). The solidwas then dried in vacuo to give the polymer supporteddicarbonyl[4-(p-methoxyphenyl)butan-2-one]chromium complex as a brownpowder (2.3 g). ν_(max) (Nujol mull)/cm⁻¹ 2059(m), 1983(w) and 1933(s)[• PPh₂Cr(C≡O)₅], 1870(s) and 1802(s) [•-PPh₂Cr(C≡O)₂Ar]², 1710 (C═O);δ_(P) (202.4 MHz, CDCl₃) 90 [• PPh₂Cr(CO)₂Ar, 40%], 56 [•-PPh₂Cr(CO)₅.22%], 29 [•-P(O)Ph₂, 11%),31 5 (•-PPh₂, 27%).

¹. represented as • PPh₂. Available from Aldrich as ‘triphenylphosphine,polymer supported’, reference 36, 645-5. Polymer is polystyrene,cross-linked with 2% divinylbenzene.

². see Table 1 for comparison of data with analogous compounds free of apolymer support.

Reduction of Ketone

The polymer supported dicarbonyl[4-p-methoxyphenyl)butan-2-one]chromiumcomplex described above (40% of 3 mmol g⁻¹=1.2 mmol g⁻¹; 1 g, 1.2 mmol)was stirred in THF (80 mL) for 1 hour, and then cooled to 0° C. Lithiumaluminium hydride (0.137 g, 3.6 mmol) was dissolved in THF (10 mL), andthe solution added dropwise to the polymer suspension via cannula. Themixture was allowed to warm to room temperature, and stirred for 16hours. Ethyl acetate (10 mL) was cautiously added, followed by water (10mL), and the mixture allowed to settle. The supernatant liquid wasremoved by cannula, and the remaining solid washed with THF (2×20 mL)and diethyl ether (20 mL). The solid was dried in vacuo, to give thepolymer supported dicarbonyl[4-p-methoxyphenyl)butan-2-ol]chromiumcomplex as a dark yellow powder (0.930 g). ν_(max.)(Nujol mull)/cm⁻¹2060(vw), 1929(vw) [• PPh₂Cr(C≡O)₅], 1876(s) and 1814(s) [•PPh₂Cr(C≡O)₂Ar], complete absence of ketone at 1710; δ_(P) (202.4 MHz,CDCl₃) 86 [• PPh₂Cr(CO)₂Ar, 24%], 54 [•-PPh₂Cr(CO)₅, trace], 22(•-P(O)Ph₂, 21%), −21 (•-PPh₂, 55%).

Decomplexation Using Pyridine

The polymer supported dicarbonyl[4-(p-methoxyphenyl)butan-2-ol]chromiumcomplex isolated above loaded (24%) diphenylphosphinopolystyrene (24% of3 mmol g⁻¹=0.72 mmol g⁻¹, 0.500 g, 0.36 mmol) was added to pyridine (10mL), the mixture was degassed, and heated at reflux under a nitrogenatmosphere for 2 hours, during which time the mixture became bright red.The mixture was allowed to cool, and the solid to settle out.Supernatant liquid was removed via cannula, and the residual solid waswashed successively with THF (2×20 mL) and diethyl ether (20 mL). Theorganic washings were concentrated in vacuo and washed through a shortpad of silica with diethyl ether. Ether was removed by evaporation toleave 4-(p-methoxyphenyl)butan-2-ol as a colourless oil (≧95% purity by¹H-nmr spectroscopy; 60 mg, 0.33 mmol, 92%). δ_(H) (270 MHz, CDCl₃) 7.14[2H, d, J 8 Hz, CHC(OMe)CH], 6.85 [2H, d, J 8 Hz, CHC(R)CH], 3.83 (1H,m, CHOH), 3.81 (3H, s, OCH ₃), 2.66 [2H, m, CH ₂CH(OH)], 1.76 (3H, m,ArCH ₂ and OH), 1.24 [3H, d, J 6 Hz, CH(OH)CH ₃].

Subtance v_(max.)Cm⁻¹ ³¹P Ref. •-PPh₂ −6.3 J. Org. Chem., 1983, 48, 326•-PPh₂═O 28.8 J. Org. Chem., 1983, 48, 326 Cr(CO)₅PPh₃ 2065, 1980, 55.3J. Am. Chem. Soc., 1940 1967, 89, 5573 58 J. Organomet. Chem., 1994,468, 143 Cr(CO)₂PPh₃C₆H₅OMe 1886s, 1827s 91.9 Polyhedron, 1988, 7, 1377Cr(CO)₂PPh₃C₆H₅NMe₂♦ 1869, 1806 93.5 Polyhedron, 1988, 7, 1377Cr(CO)₂PPh₃C₆H₅CHO♦ 1917, 1861 84.9 Polyhedron, 1988, 7, 1377MeOC₆H₄(CH₂)₂COMe. 1972vs, Synthesised as part of Cr(CO)₃ 1903vs andthis work 1710s ♦Included to represent extremes of ring electrondensity.

General Experimental

Reactions under nitrogen were performed using standard vacuum linetechniques. Diethyl ether was dried over sodium wire and tetrahydrofuranwas distilled from sodium benzophenone ketyl. Unless otherwise stated,reagents were obtained from commercial sources. IR spectra were obtainedon a Perkin-Elmer 1710 FTIR spectrometer instrument. NMR spectra wererecorded at room temperature on JEOL GSX 270 (270 MHz ¹H) and Briker DRX500 (500.0 MHz ¹H, 202.4 MHz ³¹P) spectrometers. J values are given inHz.

Experimental Details for Chromium Peptide Linker—FIG. 2

Tricarbonyl(Fmoc-Phe-OBu^(t))chromium(0) [FIG. 2, 1]

Fmoc-Phe-OBu^(t) (2 g, 4.51 mmol), hexacarbonylchromium(0) (1.04 g, 4.74mmol), anhydrous dibutyl ether (40 cm³) and anhydrous THF (10 cm³) werecombined and the mixture was thoroughly deoxygenated and heated toreflux under nitrogen for 40 h. The resulting red solution was cooledand the solvent was evaporated at reduced pressure. Columnchromatography (SiO₂, gradient elution hexane:diethyl ether 2-100%)effected purification of the following product mixture:

i) (5% diethyl ether): red solid tricarbonyl(dibenzofulvene)chromium(0)(225 mg, 0.72 mmol, 16%); mp 135° C. dec., [Found: m/z (M) 314.0037,C₁₇CrH₁₀O₃ requires 314.0035]; ν_(max)(Et₂O)/cm⁻¹ 1969vs, 1904s (C≡O);δ_(H) (300 MHz)(CDCl₃) 5.39-5.53 (2 H, m, CCH₂), 5.92-6.10 (4 H, m,ArCr(CO)₃), 7.25-7.68 (4 H, m, Ar); m/z (FAB+) 314 (M, 65%),286 (M—CO,23%), 258 (M—2CO, 68%), 230 (M—3CO, 31%), 178 (M—Cr—3CO, 36%);

ii) (5-20% diethyl ether): yellow uncomplexed Fmoc-Phe-OBu^(t) (340 mg,0.77 mmol, 17%);

iii) (100% diethyl ether): product complex as a crystalline yellow foam(820 mg, 1.42 mmol, 31%); mp 82-84° C.; [Found: m/z (M—3CO) 495.1519,C₂₈CrH₂₉NO₄ requires 495.1502]; [α]²⁰ _(D)+16.9° (c=1.0, DCM);ν_(max)(DCM)/cm⁻¹ 1969vs, 1892vs (C≡O), 1723m [C(═O)OBu^(t)]; δ_(H) (360MHz)(CDCl₃) 1.46 (9 H, s, OC(CH₃)₃), 2.6-2.9 (2 H, m, CH₂Ph), 4.18 (1 H,m, OCHH), 4.33-4.44 (2 H, m, OCHH, OCH₂CH), 4.58 (1 H, dd, J 7, 11,NCHCO₂), 4.92 (1 H, d, J 6, NH), 5.09 (5 H, m, H-2, H-3, H4, H-5, H-6),7.30-7.79 (8 H, m, H-9, H-10, H-11, H-12, H-15, H-16, H-17, H-18);δC{¹H} (90 MHz)(CDCl₃) 28.1 (OC(CH₃), 38.3 ([Cr]—PhCH₂), 47.3 (C-7),55.2 (NHCHCO₂), 66.6 (CO₂CH₂), 83.5 (OC(CH₃)₃), 90.7, 92.9, 93.4, 93.4,93.7 (C-2, C-3, C4, C-5, C-6), 107.0 (C-1), 120.0, 120.1 (C-12, C-15),124.9, 125.1, 127.2, 127.9, 127.9, 128.6 (C-9, C-10, C-11, C-16, C-17,C-18), 141.4 (C-13, C-14), 143.6, 143.8 (C-8, C-19), 155.4 (NHCO₂),169.7 (NCHCO₂), 232.7 (Cr(CO)₃); m/z (FAB+) 579 (m, 1.4%), 524 (M—2CO+H,2.6%), 495 (M—3CO, 33%), 439 (M—3CO—CMe₃+H, 8%), 179 (dibenzofulvene+H,30%), 147 (PhCH₂CHNH+H, 28%), 91 (PhCH₂, 49%), 73 (OCMe₃, 100%).

Dicarbonyl(Fmoc-Phe-OBu^(t))(polymer-PPh₂)chromium(0) [FIG. 2, 2]

To a suspension of polymer-bound triphenylphosphine (450 mg, 0.72 mmolP)at ambient temperature in anhydrous THF (200 cm³) was addedtricarbonyl(Fmoc-Phe-OBu^(t))chromium(0) (500 mg, 0.86 mmol). Underconstant nitrogen agitation, the yellow mixture was subjected toperiodic irradiation (4×10 min) over a 48 h period. The resulting deepred beads were filtered, washed thoroughly with alternate aliquots ofTHF and diethyl ether and dried in vacuo to afford the product resin(732 mg, 63% loading by mass, 0.69 mmol[Fmoc-Phe-OBu^(t)]g⁻¹);ν_(max)(Nujol)/cm⁻¹ 2005vw, 1936vw [polymer-PPh₂Cr(C≡O)₅,polymer-(PPh₂)₂Cr(C≡O)₄], 1874vs, 1828s [polymer-PPh₂Cr(C≡O)₂(Ar)],1718m [C(═O)OBu^(t)]; δ_(P) (202.5 MHz)(D₂O capillary lock) −3.3(polymer-PPh₂, 12%), 27.4 [polymer-P(O)Ph₂, 17%], 58.0[polymer-PPh₂Cr(CO)₅, 2%], 78.4 [polymer-(PPh₂)₂Cr(CO)₄, 4%], 93.2[polymer-PPh₂Cr(CO)₂(Fmoc-Phe-OBu^(t)), 70%].

Dicarbonyl(H-Phe-OBu^(t)(polymer-PPh₂)chromium(0) [FIG. 2, 3]

To a suspension of dicarbonyl(Fmoc-Phe-OBu^(t))(polymer-PPh₂)chromium(0)(250 mg, 0.17 mmol[Fmoc-Phe-OBu^(t)]) in anhydrous DCM (8 cm³) atambient temperature was added piperidine (2 cm³). After 20 mins underconstant nitrogen agitation, the beads were filtered and washed withalternate aliquots of DCM and diethyl ether. The process was repeated:re-suspension in 20% piperidine/DCM (10 cm³) for 10 mins, filtration andwashing as before afforded red beads of the product resin, takendirectly to the next coupling step; ν_(max)(Nujol)/cm-⁻¹ 1883vs, 1832s[Cr(C≡O)₂], 1720m [C(═O)OBu^(t)].

Dicarbonyl(Fmoc-Val-Phe-OBu^(t))(polymer-PPh₂)chromium(0) [FIG. 2, 4]

A solution of diisopropylethylamine (0.152 cm³, 0.87 mmol) andFmoc-Val-OH (148 mg, 0.44 mmol) in anhydrous DCM (2 cm³) was added to asuspension of dicarbonyl(H-Phe-OBu^(t))(polymer-PPh₂)chromium(0) inanhydrous DCM (2 cm³) at ambient temperature. PyBop (227 mg, 0.44 mmol)was added immediately and the mixture was left under constant nitrogenagitation for 6 h. The resulting red beads were filtered, washedthoroughly with alternate aliquots of DCM, methanol and diethyl etherand dried in vacuo to afford the product resin (265 mg, 0.61mmol[Fmoc-Val-Phe-OBu^(t)]g⁻¹); ν_(max)(Nujol)/cm⁻¹ 1883vs, 1832s[Cr(C≡O)₂], 1724m [C(═O)OBu^(t)], 1680m [CH(C═O)N]; δ_(P) (145.8MHz)(D₂O capillary lock) −4.8 (polymer-PPh₂, 8%), 26.2 [polymer-P(O)Ph₂,20%], 57.8 [polymer-PPh₂Cr(CO)₅, 3%], 75.1 [polymer-(PPh₂)₂Cr(CO)₄, 6%],91.8 [polymer-PPh₂Cr(CO)₂(Fmoc-Val-Phe-OBu^(t)), 63%].

Fmoc-Val-Phe-OBu^(t)

Dicarbonyl(Fmoc-Val-Phe-OBu^(t))(polymer-PPh₂)chromium(0) (100 mg, 0.065mmol[Fmoc-Val-Phe-OBu^(t)]) was suspended in DCM (15 cm³) in a 25 cm³round-bottomed flask equipped with a condenser and CaCl₂ drying tube andstirred at ambient temperature in air under white light (100 W) for 48h. The resulting brown suspension was filtered through celite and thepolymeric residue was washed with DCM. The combined filtrate andwashings were concentrated at reduced pressure to afford the colourlessdipeptide (36 mg, 0.065mmol, 99%); ν_(max)(neat)/cm⁻¹ 1732vs[C(═O)OBu^(t)], 1692vs [C(═O)N], 1657vs [OC(═O)N]; δ_(H) (360 MHz/CDCl₃)0.94 (6 H, m, CH(CH₃)₂), 1.39 (9 H, s, C(CH₃)₃), 2.10 (1 H, q, J 7,CH(CH₃)₂), 3.08 (2 H, d, J 6, ArCH₂), 4.06 (1 H, m, Val αH), 4.23 (1 H,dd, J 7, OCHH, OCHH or OCH₂CH), 4.33 (1 H, dd, J 7, 7, OCHH, OCHH orOCH₂CH), 4.46 (1 H, dd, J 7, 10, OCHH, OCHH or OCH₂CH), 4.78 (1 H, m,Phe αH), 5.51 (1 H, d, J 9, NH), 6.43 (1 H, d, J 8, NH), 7.14-7.78 (13H, m, Ar); δ_(C) (90 MHz)(CDCl₃) 17.9, 19.2 (CH(CH₃)₂), 28.0 (C(CH₃)₃),31.4 (CH(CH₃)₂), 38.2 (PhCH₂), 47.2 (C-7), 53.7 (Phe αC), 60.3 (Val αC),67.1 (CO₂CH₂), 82.5 (C(CH₃)₃), 120.0 (C-12, C-15), 125.2, 125.2, 127.1,127.1, 127.8, 128.5, 129.5 (C-9, C-10, C-11 , C-16, C-17, C-18, C-2,C-3, C4, C-5, C-6), 136.0 (C-1), 141.4 (C-13, C-14), 143.9 (C-8, C-19),156.4 (NCOO), 170.3, 170.8 (Val CO, Phe CO).

Experimental Details for Cobalt Linker—FIG. 3

(A) Indirect Method

(Unsaturated Organic Molecule Transition Metal Complex Formation Firstthen Attachment to Support)

Polymer-(PPh₂)_(n)(CO)_(6−n)Co₂(5-hexyn-1-ol) [FIG. 3, Scheme 1, 1]

Polymer-bound triphenylphosphine (1 g, 1.6 mmolP) was suspended atambient temperature in anhydrous THF (10 cm³) and a solution ofhexacarbonyl(5-hexyn-1-ol)cobalt(0) (1.2 g, 3.2 mmol) was added. Themixture was heated to 50° C. under constant nitrogen agitation for 4 h.The resulting deep purple beads were filtered, washed with alternatealiquots of THF and diethyl ether until the filtrate became colourless,and dried in vacuo to afford the product resin (1.52 g, 0.94±0.02mmol[5-hexyn-1-ol]g⁻¹); ν_(max)(Nujol)/cm⁻¹ 2055s, 1998vs, 1979ssh,1950s (C≡O); δ_(P) (145.8 MHz)(D₂O capillary lock) 25.6[polymer-P(O)Ph₂, 20%], 55.5[polymer-(PPh₂)_(n)Co₂(CO)_(6−n)(5-hexyn-1-ol), 80%].

(a) Esterification

Polymer-(PPh₂)_(n)(CO)_(6−n)Co₂(5hexyn-1-yl acetate) [FIG. 3, Scheme 1,2]

Polymer-(PPh₂)_(n)(CO)_(6−n)Co₂(5-hexyn-1-ol) [300 mg, 0.28mmol(5-hexyn-1-ol)] was suspended at ambient temperature in anhydrousTHF (10 cm³) under constant nitrogen agitation. Triethylamine (2.5 cm³)and acetic anhydride (1.5 cm³) were added sequentially. After 20 h atambient temperature, the resulting deep purple beads were filtered,washed thoroughly with alternate aliquots of THF and diethyl ether anddried in vacuo to afford the product resin (325 mg, 0.87±0.02mmol[5-hexyn-1-yl acetate]g⁻¹); ν_(max)(Nujol)/cm⁻¹ 2055s, 1994vs,1981ssh, 1950s (C≡O), 1734m [O(C═O)CH₃]; δ_(P) (145.8 MHz)(D₂ Ocapillary lock) 24.7 [polymer-P(O)Ph₂, 24%], 54.3[polymer-(PPh₂)_(n)Co₂(CO)_(6−n)(5-hexyn-1-yl acetate), 76%).

5-hexyn-1-yl acetate

Polymer-(PPh₂)_(n)(CO)_(6−n)Co₂(5-hexyn-1-yl acetate) (120 mg, 0.104mmol[5-hexyn-1-yl acetate]) was suspended in DCM (15 cm³) in a 25 cm³round bottomed flask equipped with a condenser and CaCl₂ drying tube andstirred at ambient temperature in air under white light (100 W) for 72h. The resulting brown suspension was filtered through celite and thepolymeric residue was washed with DCM. The combined filtrate andwashings were concentrated at reduced pressure to afford the oilycolourless product (12 mg, 0.09 mmol, 61%); ν_(max)(neat)/cm⁻¹ 3683,2931, 2359, 2249, 1732, 1367, 1242, 909, 650; δ_(H) (400 MHz)(CDCl₃)1.50-1.73 (4 H, m, CH₂CH₂CH₂O), 1.90 (1 H, t, J 3, HCCCH₂), 1.98 (3 H,s, COCH₃), 2.17 (2H, td, J 3, 7, HCCCH₂), 4.02 (2 H, t, J 7, CH₂O);δ_(C){¹H} (90MHz)(CDCl₃) 18.1 (CCCH₂), 21.0 (COCH₃), 25.0 (CH₂CH₂OCO),27.7 (CCCH₂CH₂), 64.0 (CH₂OCO), 68.8 (HCCCH₂), 83.9 (HCCCH₂), 171.2(CO).

(b) Oxidation

Polymer-(PPh₂)_(n)(CO)_(6−n)Co₂(5-hexyn-1-al) [FIG. 3, Scheme 2, 3]

Polymer-(PPh₂)_(n)(CO)_(6−n)Co₂(5-hexyn-1-ol) (500 mg, 0.47mmol[5-hexyn-1-ol]) was suspended at ambient temperature in anhydrousDCM (5 cm³) under constant nitrogen agitation. Dimethylsulfoxide (3 cm³)and triethylamine (515 mg, 0.71 cm³, 5.1 mmol) were added sequentially,followed by a solution of sulfur trioxide pyridine complex (405 mg, 2.55mmol) in dimethylsulfoxide (2 cm³). After 7 h at ambient temperature,the resulting deep purple beads were filtered, washed thoroughly withalternate aliquots of dimethylsulfoxide, DCM and diethyl ether and driedin vacuo to afford the product resin (495 mg, 0.85 mmol(5-hexyn-1-al]g-⁻¹); ν_(max)(Nujol)/cm⁻¹ 2056s, 1996vs, 1980ssh, 1951s(C≡O), 1723m (CHO); δ_(P) (145.8 MHz)(D₂O capillary lock) 24.6[polymer-P(O)Ph₂, 30%], 54.1[polymer-(PPh₂)_(n)Co₂(CO)_(6−n)(5-hexyn-1-al), 70%].

5-Hexyn-1-al

Decomplexation of the alkynyl aldehyde was effected in a procedureidentical to that described for the alkynyl ester above. Carefulevaporation of the filtrate and washings afforded the colourlessvolatile product (6 mg, 0.06 mmol, 18%); ν_(max)(neat)/cm⁻¹ 3688, 3310,2929, 2246, 1723, 1682, 1931, 1265, 643; δ_(H) (360 MHz)(CDCl₃) 1.5-1.7(2 H, m, CH₂CH₂CHO), 1.92 (1 H, t, J 3, HCCCH₂), 2.21 (2 H, dt, J 3, 7,HCCCH₂), 2.55 (2 H, dt, J 1, 7, CH₂CHO), 9.81 (1 H, t, J 1, CHO);δ_(C){¹H} (90 MHz)(CDCl₃), 17.8, 20.8 (CCCH₂CH₂), 42.6 (CH₂CHO), 69.4(CCCH₂), 79.8 (HCCCH₂), 201.8 (CHO).

(B) Direct Method

(Unsaturated Organic Molecule Completed with Transition Metal AlreadyAttached to the Support)

Polymer-(PPh₂)_(n)Co₂(CO)_(8−n) [FIG. 3, Scheme 3, 4]

Polymer-bound triphenylphosphine (2 g, 3.2 mmolP) was suspended atambient temperature in anhydrous THF (10 cm³) andoctacarbonyldicobalt(0) (2.2 g, 6.4 mmol) was added. After 1.5 h underconstant nitrogen agitation, the mixture was filtered and washed withalternate aliquots of THF and diethyl ether until the filtrate becamecolourless. Subsequent suspension in chloroform allowed separation bydecantation of a small amount of inorganic material from the deep purplebeads which were dried in vacuo to afford the product complex (2.37 g,0.91±0.06 mmol[Co₂(CO)_(x)]g⁻¹); ν_(max)(Nujol)/cm⁻¹ 2074w, 2012msh,1995s, 1985msh, 1955w, 1880vs; δ_(P) (145.8 MHz)(D₂O capillary lock) 32[polymer-P(O)Ph₂, 25%], 62 [polymer-(PPh₂)_(n)Co₂(CO)_(8−n), 75%].

Polymer-(PPh₂)_(n)(CO)_(6−n)Co₂(5-hexyn-1-ol) [FIG. 3, Scheme 1, 1]

To a suspension of polymer-(PPh₂)_(n)(CO)_(8−n)Co₂ (400 mg, 0.36mmol[Co₂(CO)_(x)]) in anhydrous dioxane (10 cm³) was added 5-hexyn-1-ol(254 mg, 0.29 cm³, 2.6 mmol). After 2 h constant nitrogen agitation at70° C., the deep purple beads were filtered, washed thoroughly withalternate aliquots of THF and diethyl ether and dried in vacuo to affordthe product complex (408 mg, 0.43±0.09 mmol[5-hexyn-1-ol]g⁻¹);ν_(max)(Nujol)/cm⁻¹ 2055w, 2009s, 1967ssh, 1948vs, 1930ssh; δ_(P) (145.8MHz)(D₂O capillary lock) −5 (polymer-PPh₂, 20%), 25 [polymer-P(O)Ph₂,50%], 55 [polymer(PPh₂)_(n)Co₂(CO)_(8−n), 30%].

For acetylation and decomplexation of the product alkynyl ester theprocedures were identical to those employed for the indirect method.

What is claimed is:
 1. A method for making a metal complex as atraceless linker between a support and an unsaturated organic moleculecomprising the formation of a π-complex bond between a transition metaland the unsaturated organic molecule and attaching of the transitionalmetal to the support before, during or after the formation of theπ-complex bond by a linking ligand that is a phosphine, phosphite orisonitrile; wherein the transition metal is cobalt or chromium.
 2. Atraceless linker system which comprises a transition metal complexattached to a support which is capable of forming a π-complex bond withan unsaturated organic molecule; wherein the transition metal isattached to the solid support by a linking ligand that is a phosphine,phosphite or isonitrile, and the transition metal is cobalt or chromium.3. A traceless linker system which comprises a transition metal complexattached to a support and an unsaturated organic molecule attached tothe transition metal through a η-complex bond; wherein the transitionmetal is attached to the solid support by a linking ligand that is aphosphine, phosphite or isonitrile, and the transition metal is cobaltor chromium.
 4. A method of attaching to a support via a transitionmetal complex traceless linker an unsaturated organic molecule, whichmethod comprises one of the following alternative first steps: (1)bonding the transition metal complex, which has bound to it through aπ-complex bond the unsaturated organic substrate molecule, with thesupport, where the transition metal complex, support or both has a groupcapable of forming a bond, linker or interaction between the transitionmetal complex and the support; (2) bonding the unsaturated organicsubstrate molecule with the transition metal complex, which is bound tothe support, by forming a π-complex between the supported transitionmetal and the unsaturated organic substrate; (3) converting an organicmolecule which is σ- or π-bonded to the transition metal, which is boundto the support, to form a π-complex between the supported transitionmetal and the unsaturated organic substrate molecule; wherein thetransition metal is attached to the solid support by a linking ligandthat is a phosphine, phosphite or isonitrile, and the transition metalis cobalt or chromium.
 5. A method of performing chemical modificationto an unsaturated organic molecule which method comprises: (A) attachingto a solid support via a transition metal complex traceless linker theunsaturated organic molecule; (B) performing at least one chemicalmodification to the unsaturated organic molecule; (C) releasing theunsaturated organic molecule from the transition metal complex tracelesslinker; wherein the transition metal is attached to the solid support bya linking ligand that is a phosphine, phosphite or isonitrile, and thetransition metal is cobalt or chromium.
 6. A method as claimed in claim5 wherein the chemical modification is a chemical synthesis being eitherby combinatorial chemistry or by multiple parallel synthesis.
 7. Amethod of tagging a support within a chemical synthesis comprising foreach reaction step desired to be labelled contacting a transition metalcomplex containing an exchangeable ligand bound to the support with atagging ligand unique for the reaction being performed; wherein thetransition metal is attached to the solid support by a linking ligandthat is a phosphine, phosphite or isonitrile, and the transition metalis cobalt or chromium.
 8. A method of tagging a support within achemical synthesis comprising for each reaction step desired to belabelled contacting a transition metal complex with a reactive groupcapable of making an analyzable modification on one of the ligands ofthe transition metal complex unique for the reaction being performed;wherein the transition metal is attached to the solid support by alinking ligand that is a phosphine, phosphite or isonitrile, and thetransition metal is cobalt or chromium.